Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus
Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus
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DOI：
10.1158/1078-0432.ccr-17-0285
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发表时间：
2017-10-01
影响因子：
11.5
通讯作者：
Loskog, Angelica
中科院分区：
文献类型：
--
作者：
Eriksson, Emma;Milenova, Ioanna;Loskog, Angelica
目的：胰腺癌是一种严重的适应症，尽管进行手术和/或联合化疗，预期生存期仍较短。检查点阻断抗体已被批准用于多种癌症适应症，但胰腺癌仍然难以治疗。然而，有临床数据表明这些患者可能对刺激 CD40 通路感兴趣。携带免疫刺激基因的溶瘤病毒代表了一种有趣的方法。在此，我们提出了 LOAd703，一种设计的腺病毒，配备有三聚化 CD40L 和 4-1BBL，分别激活 CD40 和 4-1BB 途径。由于肿瘤基质中的许多细胞，包括星状细胞和浸润性免疫细胞，表达 CD40 和一些 4-1BB，我们假设 LOAd703 激活免疫并同时调节肿瘤基质的生物学。 实验设计：LOAd703 感染肿瘤、星状细胞、内皮细胞和免疫细胞，并通过流式细胞术、蛋白质组学和功能学研究 结果：LOAd703 感染的胰腺细胞系被溶瘤杀死，并且该病毒比标准治疗吉西他滨更有效。在体内异种移植模型中，LOAd703 能有效减少已形成的肿瘤，并且可以与吉西他滨联合使用以获得额外效果。受感染的星状细胞和肿瘤细胞减少了促进肿瘤生长的因子（Spp-1、Gal-3、HGF、TGF beta 和 I 型胶原），而趋化因子则增加。受感染的内皮细胞上参与淋巴细胞迁移的分子上调。 LOAd703 强烈刺激树突状细胞产生共刺激剂、细胞因子和趋化因子，并且此类 DC 能够有效扩增抗原特异性 T 细胞和 NK 细胞。结论：LOAd703 是一种有效的免疫激活剂，可调节基质以支持抗肿瘤反应。 (C) 2017 年 AACR。
Purpose: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications, but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein, we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activates the CD40 and 4-1BB pathways, respectively. As many cells in the tumor stroma, including stellate cells and the infiltrating immune cells, express CD40 and some 4-1BB, we hypothesize that LOAd703 activates immunity and simultaneously modulates the biology of the tumor stroma.Experimental Design: Tumor, stellate, endothelial, and immune cells were infected by LOAd703 and investigated by flow cytometry, proteomics, and functional analyses.Results: LOAd703-infected pancreatic cell lines were killed by oncolysis, and the virus was more effective than standard-of-care gemcitabine. In in vivo xenograft models, LOAd703 efficiently reduced established tumors and could be combined with gemcitabine for additional effect. Infected stellate and tumor cells reduced factors that promote tumor growth (Spp-1, Gal-3, HGF, TGF beta and collagen type I), while chemokines were increased. Molecules involved in lymphocyte migration were upregulated on infected endothelial cells. Dendritic cells were robustly stimulated by LOAd703 to produce costimulators, cytokines and chemokines, and such DCs potently expanded both antigen-specific T cells and NK cells.Conclusions: LOAd703 is a potent immune activator that modulates the stroma to support antitumor responses. (C) 2017 AACR.